Perforin inhibiting benzenesulfonamide compounds, preparation and uses thereof

Abstract

Compounds of formula (1a) and pharmaceutically acceptable salts, solvates, and hydrates thereof and related methods of modulatin perforin activity on a cell: wherein Ring A is selected from a 6-10 membered aryl, 5-6 membered cycloalkyi, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, wherein the heteroaryl and heterocyclyl rings comprise at least one heteroatom selected from N, O or S; and wherein the aryl, cycloalkyi, heteroaryl or heterocyclyl rings are optionally substituted with 1 to 3 substituents selected from halo, nitro, —C-Cealkyl, —C-Ceaminoalkyl, —C-Chydroxyalkyl, -haloC-Calkyl, —C-Calkoxyl, -haloC—C<aIkoxyl, heteroaryl, aryl, hydroxyl, —C(0)Ci-C6alkyl, —OC(0)Ci-Calkyl, —CHOC(O)CrCalkyl, —C(O)OC, —CalkyI, —NHC(O)C, —C6alkyl, —NHS(O)C-Calkyl, —S(O)C-Calkyl, —S(O)NH, and —C(O)NJJ; Ring B is a 6-10 membered arylene or a 5-6 membered heteroarylene comprising at least one heteroatom selected from N, 0 or S; and wherein the aryl or heteroaryl is optionally, substituted with one or more substituents selected from —NJJ, —OJ, halo, C-Calkyl, -haloC-C6alkyl, —C-Calkoxy, -haloC-Calkoxyl, and —C(0)NJJ; Ring C is selected from a 5-10 membered heteroarylene or a 5-10 membered heterocyclene, each comprising at least one heteroatom selected from N, S and O; Ring D is an optionally substituted benzofused 9-11 membered heterocyclyl or optionally substituted ben2ofused 9-11 membered heteroaryl comprising at least one heteroatom selected from N or O; L is a linker selected from branched and unbranched C1-C4 alkylene, —S(0)2-NH—, —C(0)-NH—, —NH—C(0)-NH—, —S(0)2-NH—C(0)-NH—, —S(0)2-NH—C(0)- and —CH═CH—; wherein Rings B and C, and Rings C and D, are connected to each other via a C—C bond at any of the available C atoms on each respective ring; and J in each occurrence is independently selected from H, optionally substituted C-Calkyl or optionally substituted haloC-Calkyl.